Enantioselective Radical Reactions: Formation of Chiral Quaternary Centers

Abstract

A novel addition/trapping radical reaction to establish all-carbon chiral quaternary centers has been developed.

radical reactions - chiral Lewis acid - quaternary centers - conjugate additions - imides

References and Notes

For reviews on quaternary centers see:

1a Denissova I. Barriault L. Tetrahedron  2003,  59:  10105 

1b Christoffers J. Baro A. Angew. Chem. Int. Ed.  2003,  42:  1688 

1c Christoffers J. Mann A. Angew. Chem. Int. Ed.  2001,  40:  4591 

1d Corey EJ. Guzman-Perez A. Angew. Chem. Int. Ed.  1998,  37:  388 

1e Fuji K. Chem. Rev.  1993,  93:  2037 

1f Martin SF. Tetrahedron  1980,  36:  419 

2 Radicals in Organic Synthesis   Vol. 1 and 2:  Renaud P. Sibi MP. Wiley-VCH; Weinheim: 2001. 

3 For a recent review see: Patil K. Sibi MP. In Quaternary Stereocenters - Challenges for Organic Synthesis   Christoffers J., Baro A., Wiley-VCH; Weinheim: 2005.  p.287-313  

4a Sibi MP. Manyem S. Zimmerman J. Chem. Rev.  2003,  103:  3263 

4b Sibi MP. Porter NA. Acc. Chem. Res.  1999,  33:  163 

4c Sibi MP. Manyem S. Tetrahedron  2000,  56:  8033 

4d Parsons AF. Bar S. Chem. Soc. Rev.  2003,  251 

5a Murakata M. Jono T. Mizuno Y. Hoshino O. J. Am. Chem. Soc.  1997,  119:  11713 

5b Murakata M. Jono T. Hoshino O. Tetrahedron: Asymmetry  1998,  9:  2087 

6a Yang D. Gu S. Yan YL. Zhu NY. Cheung KK. J. Am. Chem. Soc.  2001,  123:  8612 

6b Yang D. Gu S. Yan YL. Zhao HW. Zhu NY. Angew. Chem. Int. Ed.  2002,  41:  3014 

Also see:

6c Yang D. Gao Q. Lee O.-Y. Org. Lett.  2002,  4:  1239 

6d Lin H.-H. Chang W.-S. Luo S.-Y. Sha C.-K. Org. Lett.  2004,  6:  3289 

6e Yang D. Yan Y.-L. Law K.-L. Zhu N.-Y. Tetrahedron  2003,  59:  10465 

6f Yang D. Ye X.-Y. Gu S. Xu M. J. Am. Chem. Soc.  1999,  121:  5579 

6g Yang D. Ye X.-Y. Xu M. J. Org. Chem.  2000,  65:  2208 

6h For formation of quaternary center by radical combination see: Ellison ME. Ng D. Dang H. Garcia-Garibay MA. Org. Lett.  2003,  5:  2531 

7a Imide: Sibi MP. Petrovic G. Zimmerman J. J. Am. Chem. Soc.  2005,  127:  2390 

7b Sultam: Sibi MP. Sausker JB. J. Am. Chem. Soc.  2002,  124:  984 

7c Oxazolidinones: Sibi MP. Ji J. Wu JH. Gurtler S. Porter NA. J. Am. Chem. Soc.  1996,  118:  9800 

7d Pyrrolidinones: Sibi MP. He L. Org. Lett.  2004,  6:  1749 

7e Chiral relay templates: Sibi MP. Prabagaran N. Synlett  2004,  2421 

7f Pyrazoles: Sibi MP. Shay JJ. Ji J. Tetrahedron Lett.  1997,  38:  5955 

8a Sibi MP. Prabagaran N. Ghorpade SG. Jasperse CP. J. Am. Chem. Soc.  2003,  125:  11796 

8b Sibi MP. Petrovic G. Zimmerman J. J. Am. Chem. Soc.  2005,  127:  2390 

8c For the use of imide templates in conjugate additions see: Sammis GM. Jacobsen EN. J. Am. Chem. Soc.  2003,  125:  4442 ; and references cited therein.

9a For addition/trapping experiments from our laboratory, see: Sibi MP. Ji J. J. Org. Chem.  1996,  61:  6090 

9b Sibi MP. Chen J. J. Am. Chem. Soc.  2001,  123:  9472 

9c Sibi MP. Manyem S. Subramaniam R. Tetrahedron  2003,  59:  10575 

For examples of radical reactions where stereocenter α to a carbonyl is established, see:

10a Stereochemistry of Radical Reactions   Curran DP. Porter NA. Giese B. VCH; Weinheim: 1995. 

10b Durkin K. Liotta D. Rancourt J. Lavallée J.-F. Boisvert L. Guindon Y. J. Am. Chem. Soc.  1992,  114:  4912 

10c Guindon Y. Houde K. Prevost M. Cardinal-David B. Landry SR. Daoust B. Bencheqroun M. Guerin B. J. Am. Chem. Soc.  2001,  123:  8496 

10d Curran DP. Abraham AC. Tetrahedron  1993,  49:  4821 

10e Curran DP. Ramamoorthy PS. Tetrahedron  1993,  49:  4841 

10f Curran DP. Geib S. De Mello N. Tetrahedron  1999,  55:  5681 

For a reaction with tiglates see:

10g Kopping B. Chatgilialoglu C. Zehnder M. Giese B. J. Org. Chem.  1992,  57:  3994 

10h Watanabe Y. Mase N. Furue R. Toru T. Tetrahedron Lett.  2001,  42:  2981 

10i Wu JH. Zhang G. Porter NA. Tetrahedron Lett.  1997,  38:  2067 

10j Wu JH. Radinov R. Porter NA. J. Am. Chem. Soc.  1995,  117:  11029 

11

The ethyl addition products were formed in minor amounts depending on the chiral Lewis acid and/or template employed for the reaction.

12a Kanemasa S. Oderaotoshi Y. Yamamoto H. Tanaka J. Wada E. Curran DP. J. Org. Chem.  1997,  62:  6454 

12b Iserloh U. Curran DP. Kanemasa S. Tetrahedron: Asymmetry  1999,  10:  2417 

12c Iserloh U. Oderaotoshi Y. Kanemasa S. Curran DP. Org. Synth.  2003,  80:  46 

13a Sibi MP. Ji J. J. Org. Chem.  1997,  62:  3800 

13b Sibi MP. Shay JJ. Liu M. Jasperse CP. J. Am. Chem. Soc.  1998,  120:  6615 

13c Sibi MP. Ma Z. Jasperse CP. J. Am. Chem. Soc.  2005,  127:  5764 

13d Sibi MP. Itoh K. Jasperse CP. J. Am. Chem. Soc.  2004,  126:  5366 

13e Sibi MP. Stanley LM. Jasperse CP. J. Am. Chem. Soc.  2005,  127:  8276 

14

General Procedure for the Addition/Trapping Reaction
To a suspension of Lewis acid (0.2 mmol) in 1.5 mL of CH₂Cl₂ was added the chiral ligand (0.2 mmol) and stirred at r.t. for 2 h resulting in a clear solution. Substrate (0.2 mmol) in CH₂Cl₂ was added to above chiral Lewis acid and the reaction cooled to -78 °C and stirred for 1 h. The radical precursor (6 mmol) was added, followed by addition of allyltributyltin (0.62 mL, 2 mmol), Et₃B (1 mL, 1 mmol) and 10 mL of O₂. The reaction was allowed to reach r.t. over 12 h. The reaction mixture was diluted with CH₂Cl₂ (20 mL) and silica gel (4 g) was added. After removal of the solvent, the silica gel was washed with hexane (30 mL), followed by hexane-EtOAc (1:1, 30 mL). The hexane-EtOAc solution was concentrated to give the crude, which was purified by flash chromatography to give pure product. The enantio-meric purity was determined by chiral GC. Conditions for GC analyses: Supelco β-Dex 225 column, 30 m in length, 0.25 mm inner diameter, isotherm temperature program, and He as carrier gas (1 mL/min).
2-Isobutyl-2-methylpent-4-enoic Acid (2,2-Dimethyl-propionyl)amide (4)
Mp 67-68 °C; R _f = 0.3 (hexane-EtOAc, 4:1); 70% ee (1 mL/min, T = 80 °C, t _R1 = 42 min, t _R2 = 43.6 min). IR (film): 1758, 1478, 1453 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 8.25 (br s, 1 H), 5.76 (m, 1 H), 5.15-5.10 (m, 2 H), 2.39 (dd, J = 14.0, 7.0 Hz, 1 H), 2.18 (dd, J = 14.5, 7.5 Hz, 1 H), 1.72 (m, 1 H), 1.62 (dd, J = 14.5, 7.0 Hz, 1 H), 1.41 (dd, J = 14.5, 5.5 Hz, 1 H), 1.24 (s, 9 H), 1.21 (s, 3 H), 0.92 (d, J = 6.5 Hz, 3 H), 0.87 (d, J = 6.5 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 175.0, 174.3, 133.1, 119.3, 48.5, 47.5, 44.7, 40.5, 27.1, 24.7, 24.5, 23.5, 21.3. HRMS: m/z calcd for C₁₅H₂₇NO₂Na⁺: 276.1933; found: 276.1932.
2-(2,2-Dimethylpropyl)-2-methylpent-4-enoic Acid (2,2-Di­methylpropionyl)amide (18)
Mp 73-74 °C; R _f = 0.33 (hexane-EtOAc, 4:1); 73% ee (1 mL/min, T = 75 °C, t _R1 = 91.3 min, t _R2 = 93.1 min). IR (film): 3054, 1758, 1478 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 8.29 (br s, 1 H), 5.73 (m, 1 H), 5.15-5.08 (m, 2 H), 2.39 (dd, J = 14.0, 6.5 Hz, 1 H), 2.13 (dd, J = 13.5, 8.0 Hz, 1 H), 1.87 (d, J = 14.5 Hz, 1 H), 1.45 (d, J = 15.0 Hz, 1 H), 1.29 (s, 3 H), 1.25 (s, 9 H), 0.96 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 174.9, 174.3, 132.8, 119.5, 52.7, 47.9, 47.1, 40.5, 31.7, 31.2, 27.1, 21.7. HRMS: m/z calcd for C₁₆H₂₉NO₂Na⁺: 290.2090; found: 290.2080.
2-Cyclohexylmethyl-2-methylpent-4-enoic Acid (2,2-Dimethyl-propionyl)amide (20)Mp 90-91 °C; R _f = 0.33 (hexane-EtOAc, 4:1); 64% ee (1.6 mL/min, T = 123 °C, t _R1 = 46.3 min, t _R2 = 46.9 min). IR (film): 3054, 1758, 1479 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.24 (br s, 1 H), 5.75 (m, 1 H), 5.16-5.08 (m, 2 H), 2.38 (dd, J = 14.0, 6.8 Hz, 1 H), 2.18 (ddt, J _d = 14.0, 8.0 Hz, J _t = 1.2 Hz, 1 H), 1.69-1.56 (m, 7 H), 1.40-1.35 (m, 2 H), 1.25 (s, 9 H), 1.20 (s, 3 H), 1.18-1.06 (m, 2 H), 0.99-0.88 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.0, 174.3, 133.1, 119.2, 47.38, 47.35, 44.7, 35.1, 34.3, 34.2, 27.1, 26.31, 26.27, 26.1, 21.5. HRMS: m/z calcd for C₁₈H₃₁NO₂Na⁺: 316.2246; found: 316.2256.